Derivatives of γ-cylodextrin

ABSTRACT

Novel derivatives of γ-cyclodextrin, their preparation and their use as complexants and solubilizers. Compositions containing the novel γ-cyclodextrin derivatives and method of preparing such compositions.

This is a division of application Ser. No. 833,622, filed Feb. 27, 1986,now U.S. Pat. No. 4,764,604, issued Aug. 16, 1988.

BACKGROUND OF THE INVENTION

The present invention is concerned with new ethers of γ-cyclodextrin,their preparation and their use as complexants for chemicals andpharmaceuticals.

γ-cyclodextrin (γ-CD) is a cyclic oligosaccharide consisting of 8glucose units which are joined together by α(1-4) linkages. ##STR1##γ-CD is prepared by the enzymatic cleavage and religation of starch anda subsequent separation from the thus obtained cyclodextrin mixturecontaining i.a. α-cyclodextrin (containing 6 glucose units),β-cyclodextrin (β-CD) (7 glucose units) and γ-cyclodextrin (γ-CD).

Cyclodextrins are known in the art to possess the ability to forminclusion complexes and to have concomitant solubilizing properties. Anexhaustive review which describes such complexes and their propertiescan be found in W. Sanger, Angewandte Chemie, 92, 343-361 (1981).

Derivatives of cyclodextrins are also known to possess theabove-mentioned properties. Said derivatives have been reviewed in anarticle by A. P. Croft and R. A. Bartsch in Tetrahedron, 39, 1417-1474(1983). More particularly, the German Offenlegungsschrift DE No. 3118218discloses the 2,6-dimethyl derivatives of β-CD, while in U.S. Pat. No.3,459,731 there are described hydroxyethyl, hydroxypropyl andhydroxypropyl/hydroxyethyl ethers of β-CD. Furthermore, in U.S. patentapplication Ser. No. 6-603, 839 there is described the use of specificderivatives of cyclodextrines to improve the systemic administration ofsex hormones. Most of the cyclodextrin derivatives presently known inthe art are derived from β-CD, while the derivatives of α-CD andparticularly of γ-CD remain relatively unknown.

The use of derivatives of β-CD has the following advantages. β-CD isonly poorly water soluble and therefore it is disadvantageous to use itas a complexant and solubilizer. Derivatives of β-CD on the other hand,due to their increased solubility, are more suitable complexants andsolubilizers. In contrast herewith, α-CD and γ-CD having an excellentwater solubility do not need such substitutions. Hence, it is obvious touse unsubstituted γ-CD (and α-CD) as complexant and solubilizer.Particularly for γ-CD, a number of such complexes with various usefulcompounds can be found in e.g. Int. J. Pharm. 10, 1-15 (1982) withsteroid hormones, in Acta Pharm. Suec. 20, 11-20 (1983) withflurtripofen, in Chem. Pharm. Bull. 31, 286-291 (1983) with spirolactonand in Acta Pharm. Suec. 20, 287-294 (1983) with proscillaridin.

γ-CD does not form such inclusion complexes with any given compound.Often, such complexation is onlyu established in the lower concentrationrange. At higherr concentrations of γ-CD, the formed complex isprecipitated.

It has now been found that an appropriately alkylated, hydroxyalkylated,carboxyalkylated or (alkyloxycarbonyl)alkylated form of γ-CD or a mixedether thereof prevents the crystallization of such complexes. Theadvantages of γ-CD over its lower homologues, i.e. its larger cavityresulting in a superior propensity to form inclusion complexes, itsfavourable toxicological properties and the fact that it can be cleavedenzymatically by α-amylase (in contrast with β-CD), can therefore fullybe exploited.

γ-CD contains three free hydroxy functions per glucose unit which cancompletely or partially be derivatized. In view of this, the averagedegree of substitution (D.S.) is introduced, which is the average numberof substituted hydroxy functions per glucose unit. Said D.S. can varyfrom its minimal value 0.125 up to its maximal value 3. In the lattercase all 24 hydroxy groups are substituted, while in the former caseonly one is substituted. A minimal D.S. is especially preferred whenγ-CD is used as solubilizer of pharmaceuticals for use in parenteralapplications, while a higher D.S. is preferred when used in technicalapplications, such as, for example, for pesticides or enzymes. In thelatter instance, the higher D.S. causes that also those hydroxy groupsare functionalized which are located in the cavity of the γ-CD molecule.Consequently, the diameter of the cavity is decreased. By selecting theappropriate D.S. the size of the cavity can be adapted in order toobtain the optimum space required for a certain molecule toappropriately fit into the cavity of the cyclodextrin.

When introducing hydroxyalkyl substitutions on γ-CD, the hydroxyfunction of the thus obtained hydroxyalkyl ether group can further behydroxyalkylated, generating multiple substitutions on one particularOH-group. In such cases the term average molar substitution (M.S.) isintroduced. Said M.S. is defined as the average number of moles of thesubstituting agent per glucose unity. In view of this, it is evidentthat the M.S. can be greater than 3 and has, theoretically, no upperlimit.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is concerned with novel γ-CD derivatives, saidnovel γ-CD derivatives being γ-CD substituted with C₁ -C₆ alkyl, hydroxyC₁ -C₆ alkyl, carboxy C₁ -C₆ alkyl or C₁ -C₆ alkyloxycarbonylC₁ -C₆alkyl or mixed ethers thereof.

In the foregoing definitions the term "C₁ -C₆ -alkyl" is meant toinclude straight and branched saturated hydrocarbon radicals, havingfrom 1 to 6 carbon atoms, such as, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike.

Preferred compounds are those γ-CD derivatives being γ-CD substitutedwith C₁ -C₃ alkyl, hydroxy C₂ -C₄ alkyl, carboxy C₁ -C₂ alkyl or (C₁ -C₂alkyloxycarbonyl)C₁ -C₂ alkyl or mixed ethers thereof.

Particularly preferred new compounds are the methyl, ethyl, isopropyl,hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxymethyl andcarboxyethyl substituted γ-cyclodextrins and further the(methyl)(hydroxyethyl), (methyl)(hydroxpropyl) and(methyl)(hydroxyethyl)(carboxymethyl) substituted γ-cyclodextrins havinga D.S or M.S. of from 0.125 to 3, more preferably of from 0.3 to 2.

The compounds of the present invention can generally be prepared byreacting the starting γ-CD with an appropriate O-alkylating agent or amixture of such agents in a concentration being selected so that thedesired D.S. is obtained. The said reaction is preferably conducted in asuitable solvent in the presence of an appropriate base. An appropriateO-alkylating agent is, for example, an alkyl, hydroxyalkyl, carboxyalkylor (alkyloxycarbonyl)alkyl halide or sulfonate, e.g. methyl chloride,ethyl bromide, propyl methylsulfonate, ethyl chloroacetate,α-chloroacetic acid; or an oxirane, e.g. oxirane, methyloxirane.Suitable solvents are, for example, water; an alcohol or polyalcohol,e.g. methanol, ethanol, 1-propanol, 2-propanol, 1-butanol,1,2-ethanediol, 1,2-propanediol and the like; a ketone, e.g.2-propanone, 2butanone, 4-methyl-2-pentanone, and the like; an ether orpolyether, e.g. ethoxyethane, 2-(2-propyloxy)propane, tetrahydrofuran,1,2-dimethoxyethane and the like; and C₁ -C₄ -alkyloxy-C₂ -C₃ -alkanoland mixtures of such solvents. An appropriate base is, for example, analkali or earth alkaline metal hydroxide, e.g. sodium hydroxide,potassium hydroxide; or an alkali or earth alkaline metal hydride oramide, e.g. sodium hydride, calcium hydride, sodium amide and the likebases.

Preferably the said O-alkylation reaction is conducted with 0.1 to 3parts by weight of water per part by weight γ-CD in case there is noorganic solvent used, and with 1 to 40 parts by weight organic solventper part by weight γ-CD in case no water is used.

In a particularly preferred way of preparing the compounds of thepresent invention, the reaction mixture containing the starting γ-CD,the solvent, base and O-alkylating agent is heated in an autoclave at atemperature comprised between 30° and 200° C. Depending on thereactivity of the O-alkylating agent, the reaction mixture is allowed toreact at this temperature for 15 minutes up to 24 hours. Subsequently,the mixture is acidified and the reaction product is isolated andpurified by standard separation and purification procedures such as, forexample, column chromatography, ultra filtration, centrifugation, anddried.

The compounds of the present invention can also be converted into eachother. For example, the (alkyloxycarbonyl)alkyl substitutedγ-cyclodextrines may conveniently converted to the correspondingcarboxyalkyl substituted γ-cyclodextrines following art-knownsaponification procedures, e.g. by treating the starting compounds withan aqueous acidic or basic solution.

The compounds of the present invention are useful due to their abilityto form inclusion complexes having a stabilizing effect on the complexedcompounds, and due to their concomitant solubilizing activity. Compoundsexhibiting a significantly increased water solubility and improvedstability after having been transferred to inclusion complexes with theabove-mentioned γ-CD derivatives, are those having the required shapeand size, i.e. which fit into the cavity. The size of the cavity can beadapted by selecting the appropriate γ-CD derivatives having a suitableD.S. Examples of such compounds are, for example, non-steroidanti-rheumatic agents, steroids, cardiac glycosides and derivatives ofbenzodiazepine, benzimidazole, piperidine, piperazine, imidazole,triazole, pyridazine, 1,2,4-triazinedione or2,3,5,6-tetrahydro-imidazo[2,1-b]thiazoles, or amides, hydratropic acidderivatives or trialkylamines, whereby the derivatives ofbenzodiazepine, benzimidazole, piperidine, piperizine, imidazole,triazole, pyridazine, 1,2,4-triazinedione or2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole, or amides, hydratropic acidderivatives or trialkylamines are preferred.

Useful benzimidazole derivatives are thiabendazole, fuberidazole,ciclobendazole, oxibendazole, parbendazole, cambendazole, mebendazole,fenbendazole, flubendazole, albendazole, oxfendazole, nocodazole andastemizole.

Suitable piperidine derivatives are diphenoxylate, phenoperidine,haloperidol, haloperidol decanoate, bromperidol decanoate, bromperidol,moperone, trifluperidol, pipamperone, piritramide, fentanyl, benperidol,droperidol, benzitramide, benzetimide, domperidone, sufentanil,carfentanil, alfentanil, dexetimide, milenperone, difenoxin,fluspirilene, penfluridol, pimozide, lorcainide, loperamide, astemizole,ketanserine, levocabastine, cisapride, altanserin, ritanserin,3-[2-[4-(4-fluorobenzoyl)-1-piperidinyl]ethyl]-2,7-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one,3-[2-[4-[bis(4-fluorophenyl)methylene]-1-piperidinyl]ethyl]-2methyl-4H-pyrido[1,2-a]pyrimidin-4-oneand3-[2-[4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one.Suitable piperazine derivatives include azaperone, fluanisone,lidoflazine, flunarizine, mianserine, oxatomide, mioflazine, clocinizineand cinnarizine.

Examples of suitable imidazol derivatives are metronidazole, ornidazole,ipronidazole, tinidazole, isoconazole, nimorazole, miconazole,burimamide, metiamide, metomidate, enilconazole or imazalil, etomidate,econazole, clotrimazole, carnidazole, cimetidine, doconazole,sulconazole, parconazole, orconazole, butoconazole, triadiminole,tioconazole, valconazole, fluotrimazole, ketoconazole, oxiconazole,lombazole, bifonazole, oxmetidine, fenticonazole, tubulazole and(Z)-1-[2-chloro-2-(2,4-dichlorophenyl)ethenyl]-1H-imidazole.

As suitable triazole derivatives there may be mentioned virazole,azaconazole, etaconazole, propiconazole, penconazole, itraconazole, andterconazole.

Useful pyridazine derivatives are, for example,3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazine,3-methoxy-6-[4-(3-methylphenyl)-1piperazinyl]pyridazine and thecompounds of Publ. Eur. Pat. Appl. No. 0,156,433.

Useful 1,2,4-trizinediones are, for example,2-chloro-α-(4-chlorophenyl)-4-(4,5dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile,2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrileand the compounds of Publ. Eur. Pat. Appl. No. 0,170,316.

Useful trialkylamines are, for example, diisopromine, prozapine.

Useful 2,3,5,6-tetrahydro-imidazo[2,1-b]thiazoles comprise, for example,tetramisole or levamisole.

Useful amides are, for example, closantel, ambucetamide, isopropamide,buzepide metiodide, dextromoramide.

A useful hydratropic acid derivative is, for example, suprofen.

Particularly valuable pharmaceutical compositions are obtained whenconverting etomidate, ketoconazole, tubulazole, itraconazole,levocabastine or flunarizine into a water-soluble form using the complexforming agents of the invention. Such compositions are therefore aspecial subject of the present invention.

The invention is further directed to a method of preparing compositionsof sparingly water-soluble or water-instable compounds which method ischaracterized by dissolving the γ-cyclodextrin ether in water and addingthereo the selected compound as well as optionally drying the solutionof the formed inclusion compound using methods known per se. Formationof the solution may preferably take place at temperatures between 15°and 35° C.

The drug is suitably added batchwise. The water may further comprisephysiologically compatible compounds such as sodium chloride, potassiumnitrate, glucose, mannitol, sorbitol, xylitol or buffers such asphosphate, acetate or citrate buffer.

Using γ-cyclodextrin ethers in accordance with the invention it ispossible to prepare commonly known application forms of drugs for oral,parenteral, topical, rectal or vaginal application, e.g. infusion andinjection solutions, drop solutions (e.g. eye drops or nasal drops),sprays, tablets, powders, capsules, aerosols, sirups, jellies,ointments, medical baths, rectalia and vaginalia.

The aqueous solutions may further comprise suitable physiologicallycompatible preserving agents such as, for example, quaternary ammoniumsoaps, chlorbutanol, phenoxetol, bromopol, and the like, and alsoantioxidantia, such as, for example, ascorbic acid.

For the preparation of solid formulations the solutions of the inclusioncompounds are dried using conventional methods; thus the water may beevaporated in a rotation evaporator or by lyophilisation. The residue ispulverized and, optionally after addition of further inert ingredients,converted into uncoated or coated tablets, suppositories, capsules,creams or ointments.

EXAMPLES

The following examples are meant to illustrate and not to limit thepresent invention in all its aspects. Unless stated otherwise, all partstherein are by weight.

A. Preparation Examples EXAMPLE 1

1 Part of γ-CD and a solution of 1.5 parts of sodium hydroxide in 1.5parts of water were mixed in an autoclave. Then there were added 3 partsof methyl chloride and 0.5 parts of methyloxirane. The mixture washeated for 1 hour at 65° C. and subsequently for 2 hours at 100° C.After cooling, the remaining methyloxirane was expelled and the reactionmixture was neutralized with hydrochloric acid. The volatile componentswere evaporated and the remainder was filtered. The filtrate wasliberated from sodium chloride over an ion exchanger and subsequentlyfreeze-dried, yielding the (methyl)(hydroxypropyl) derivative of γ-CD.Following the same procedures and using the appropriate startingmaterials the (ethyl)(hydroxyethyl) derivatives of γ-CD was alsoprepared.

EXAMPLE 2

In an autoclave there were mixed 2.5 parts of 1,2-dimethoxyethane. 1part of γ-CD and a solution of 1 part of sodium hydroxide in 1.2 partsof water. To this mixture, there were added 2 parts of oxirane and thewhole was heated to 110° C. for 5 hours. After cooling, the remainingoxirane was expelled and the reaction mixture was neutralized withhydrochloric acid. The volatile components were evaporated and theremainder was filtered. The filtrate was subsequently liberated fromsodium chloride over an ion exchanger and subsequently freeze-dried,yielding the hydroxyethyl derivative of γ-CD with a M.S. of 0.77.

Following the same procedures and using the appropriate startingmaterials there was also prepared the 2-hydroxypropyl derivative of γ-CDwith a M.S. of 0.66.

EXAMPLE 3

1 Part of γ-CD, 3 parts of 1,2-dimethoxyethane and 1.5 parts of sodiumhydroxide in 1.5 parts of water were mixed in an autoclave.Subsequently, there were added 4 parts of chloromethane and the wholewas heated at 120° C. for 4 hours. After cooling the reaction mixturewas neutralized with hydrochloric acid and the volatile componentsevaporated. The remainder was filtered and the filtrate was liberatedfrom sodium chloride over an ion exhanger and subsequently freeze-dried,yielding the methyl derivative of γ-CD with a D.S. of 1.49.

Following the same procedures and using the appropriate startingmaterials there were also prepared the methyl derivative of γ-CD with aD.S. of 0.13; the carboxymethyl derivative of γ-CD with a D.S. of 0.86;and the (ethoxycarbonyl)methyl derivative of γ-CD; the ethyl derivativeof γ-CD; the butyl derivative of γ-CD; the isobutyl derivative of γ-CD;the isopropyl derivative of γ-CD; the carboxyethyl derivative of γ-CD;the 3-hydroxypropyl derivative of γ-CD; and the 4-hydroxybutylderivative of γ-CD.

B. Examples Illustrating the Properties of the γ-CD Derivatives EXAMPLE4

Starting from a 5% stock solution of a particular γ-CD derivative in aphosphate buffer of pH 7.4, a dilution series was obtained withconcentrations varying of from 0% to 5% with 0.5% steps. 3 ml of thesesolutions were pipetted into a closed container containing anappropriate amount of progesteron. After 5 days shaking at 25° C., thethus obtained mixture was filtered over a membrane filter (porediameter: 0.22 μm), and the content of progesteron was determined withhigh pressure liquid chromatography (using a column of 25 cm length; 5mm internal diameter; packed with 5 μm ODS-hypersil (RP-18); eluent:acetonitrile/water; U.V. detection). The results of these concentrationmeasurements for a number of the γ-CD derivatives of the presentinvention and for unsubstituted γ-CD gathered in the following table.

                                      TABLE                                       __________________________________________________________________________    Content of progesteron in solutions containing various                        concentrations of γ-CD derivative and γ-CD                        concentration                                                                        content of progesteron in μg/ml                                     of γ-CD                                                                             methyl methyl carboxy-                                                                             hydroxy                                                                              hydroxy                               derivative                                                                           unsubsti-                                                                          substi-                                                                              substi-                                                                              methyl ethyl  propyl                                in % (weight                                                                         tuted                                                                              tuted  tuted  subst. subst. subst.                                by volume)                                                                           γ-CD                                                                         D.S. = 0.13                                                                          D.S. = 1.49                                                                          M.S. = 0.86                                                                          M.S. = 0.77                                                                          M.S. = 0.66                           __________________________________________________________________________    0      5.9  5.9    5.9    5.9    5.9    5.9                                   0.5    425  488    379    102    234    302                                   1      343  972    748    209    452    582                                   1.5    275  1458   1144   313    673    872                                   2      203  1902   1470   417    860    1165                                  2.5    163  2149   1888   517    1055   1431                                  3      93   2258   2260   610    1291   1704                                  3.5    60   2392   2686   79     1472   1987                                  4      54   2592   3050   796    1722   2287                                  4.5    46   2627   3411   891    1817   2595                                  5      45   2602   3876   979    2065   2865                                  __________________________________________________________________________

EXAMPLE 5

Following the procedures described in example 4 the content of3-chloro-6-[3,6-dihydro-4-(3-methylphenyl)-1(2H)-pyridinyl]pyridazinewas determined in solutions containing various concentrations of γ-CDderivatives. Said pyridazine compound is described in Published Europ.Pat. Appl. No. 0,156,433 as a useful anti-viral agent.

    ______________________________________                                                 content of 3-chloro-6-[3,6-dihydro-4-                                concentration                                                                          (3-methylphenyl)-1(2 .sub.-- H)--pyridinyl]                          of γ-CD                                                                          pyridazine in μg/ml                                               derivative           methyl     hydroxypropyl                                 in % (weight                                                                           unsubstituted                                                                             substituted                                                                              substituted                                   by volume)                                                                             γ-CD  D.S. = 1.49                                                                              M.S. = 0.66                                   ______________________________________                                        0        0.4         0.4        0.4                                           1        2.0         2.0        1.5                                           2.5      0.8         8.0        4.5                                           3.5      --          12.6       7.0                                           5        0.8         20.0       10.0                                          ______________________________________                                    

C. Composition Examples EXAMPLE 6

In 100 ml water 7 g hydroxyethyl-γ-CD (M.S.=0.77) and 0.5 gmedroxyprogesterone acetate were dissolved. The water was evaporated. 75mg of the residue was powdered and mixed with 366 mg CaHPO₄.2H₂ O, 60 mgcorn starch, 120 mg cellulose powder (microcrystalline), 4.2 mg highlydispersed silica (Aerosil® 200) and 4.8 mg magnesium stearate andpressed to a tablet.

EXAMPLE 7

5 g hydroxyethyl γ-cyclodextrin (M.S.=0.77) and 0.5 g lidocaine weredissolved in 100 ml of a physiological sodium chloride solution at 30°C. and filtered through a membrane filter (0.45 microns). The solutionwas filled into ampules and sterilized.

What is claimed is:
 1. A composition comprising an active ingredient anda γ-cyclodextrin ether or mixed ether wherein the ether substituents areC₁ -C₆ alkyl, hydroxy C₁ -C₆ alkyl, carboxy C₁ -C₆ alkyl or (C₁ -C₆alkyloxycarbonyl)C₁ -C₆ alkyl; provided that neither methyl norhydroxypropyl is a sole substituent.
 2. A composition according to claim1 wherein the ether substituents are C₁ -C₃ alkyl, hydroxy C₂ -C₄ alkylor carboxy C₁ -C₂ alkyl.
 3. A composition according to claim 1 whereinthe ether substituents are methyl, ethyl, isopropyl, hydroxyethyl,hydroxypropyl, hydroxybutyl, carboxymethyl or carboxyethyl.
 4. Acomposition comprising an active ingredient and a γ-cyclodextrin etheror mixed ether wherein the ether substituents are C₁ -C₃ alkyl, hydroxyC₂ -C₄ alkyl or carboxy C₁ -C₂ alkyl and wherein the degree ofsubstitution is in the range of 0.125 to less than
 2. 5. A compositionaccording to claim 4 wherein the ether substituent is hydroxyethyl orhydroxypropyl and the average molar substitution is in the range of 0.3to less than one.
 6. A composition according to claim 1, wherein theactive ingredient is a drug.
 7. A composition according to claim 4,wherein the active ingredient is a drug.
 8. A composition according toclaim 5, wherein the active ingredient is a drug.
 9. A compositionaccording to claim 6, wherein the drug is a non-steroid anti-rheumaticagent, a steroid, a cardiac glycoside or a derivative of benzodiazepine,benzimidazole, piperidine, piperazine, imidazole, triazole, pyridazine,1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole orhydratropic acid, or an amide or trialkylamine derivative.
 10. Acomposition according to claim 7, wherein the drug is a non-steroidanti-rheumatic agent, a steroid, a cardiac glycoside or a derivative ofbenzodiazepine, benzimidazole, piperidine, piperazine, imidazole,triazole, pyridazine, 1,2,4-triazinedione,2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole or hydratropic acid, or anamide or trialkylamine derivative.
 11. A composition according to claim8, wherein the drug is a non-steroid anti-rheumatic agent, a steroid, acardiac glycoside or a derivative of benzodiazepine, benzimidazole,piperidine, piperazine, imidazole, triazole, pyridazine,1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole orhydratropic acid, or an amide or trialkylamine derivative.
 12. Acomposition according to claim 6, wherein the drug is a derivative ofbenzodiazepine, benzimidazole, piperidine, piperazine, imidazole,triazole, pyridazine, 1,2,4-triazinedione,2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole or hydratropic acid, or anamide or trialkylamine derivative.
 13. A composition according to claim7, wherein the drug is a derivative of benzodiazepine, benzimidazole,piperidine, piperazine, imidazole, triazole, pyridazine,1,2,4-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole orhydratropic acid, or an amide or trialkylamine derivative.
 14. Acomposition according to claim 8, wherein the drug is a derivative ofbenzodiazepine, benzimidazole, piperidine, piperazine, imidazole,triazole, pyridazine, 1,2,4-triazinedione,2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole or hydratropic acid, or anamide or trialkylamine derivative.
 15. A composition according to claim6, wherein the drug is selected from the group consisting of etomidate,ketoconazole, itraconazole and flunarizine.
 16. A composition accordingto claim 7, wherein the drug is selected from the group consisting ofetomidate, ketoconazole, itraconazole and flunarizine.
 17. A compositionaccording to claim 8, wherein the drug is selected from the groupconsisting of etomidate, ketoconazole, itraconazole and flunarizine. 18.A composition according to claim 4, wherein the active ingredient is adrug.
 19. A composition according to claim 18, wherein the drug is anon-steroid anti-rheumatic agent, a steroid, a cardiac glycoside or aderivative of benzodiazepine, benzimidazole, piperidine, piperazine,imidazole, triazole, pyridazine, 1,2,4-triazinedione,2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole or hydratropic acid, or anamide or trialkylamine derivative.
 20. A composition according to claim18, wherein the drug is a derivative of benzodiazepine, benzimidazole,piperidine, piperazine, imidazole, triazole, pyridazine,1,2,4,-triazinedione, 2,3,5,6-tetrahydro-imidazo[2,1-b]thiazole orhydratropic acid, or an amide or trialkylamine derivative.
 21. Acomposition according to claim 4, wherein the drug is a derivative ofbenzodiazepine, benzimidazole, piperidine, piperazine, imidazole,triazole, pyridazine, 1,2,4-triazinedione,2,3,5,6-tetrahydra-imidazo[2,1-b]thiazole or hydratropc acid, or anamide or trialkylamine derivative.
 22. A composition according to claim4, wherein the drug is selected from the group consisting of etomidate,ketoconazole, itraconazole and flunarizine.
 23. A method of preparing acomposition according to claim 1, characterized in that theγ-cyclodextrin ether is dissolved in water and that the activeingredient is added whereafter the thus obtained solution is optionallydried.
 24. A method of preparing a composition according to claim 2characterized in that the γ-cyclodextrin ether is dissolved in water andthat the active ingredient is added whereafter the thus obtainedsolution is optionally dried.
 25. A method of preparing a compositionaccording to claim 4 characterized in that the γ-cyclodextrin ether isdissolved in water and that the active ingredient is added whereafterthe thus obtained solution is optionally dried.
 26. A method accordingto claim 23, wherein the residue after removal of the solvent ispulverized and, optionally after addition of further ingredients,converted into a solid form for administration.
 27. A method accordingto claim 26, wherein further physiologically acceptable substances areadded to the water.
 28. A method according to claim 27, wherein sodiumchloride, glucose, mannitol, sorbitol, xylitol or a phosphate or citratebuffer are added to the water.
 29. A method according to claim 24,wherein the residue after removal of the solvent is pulverized and,optionally after addition of further ingredients, converted into a solidform for administration.
 30. A method according to claim 29, whereinfurther physiologically acceptable substances are added to the water.31. A method according to claim 30, wherein sodium chloride, glucose,mannitol, sorbitol, xylitol or a phosphate or citrate buffer are addedto the water.